The use and abuse methamphetamine (MA) and methylenedioxymethamphetamine (MDMA) has been a long-standing societal and public health problem. Individuals use these drugs because of their stimulant and euphoric properties. In addition to problems associated with long-term use, these amphetamine derivatives have acute toxic effects that are associated with substantial morbidity and lethality. Consequently, MA and MDMA are tightly regulated by the Drug Enforcement Agency (DEA). These drugs are chemically similar to the naturally- occurring substance cathinone, derived from the khat plant, which is also now being abused in the United States. Simple chemical modifications of these and similar compounds produce a variety of structurally related synthetic psychoactive cathinones (SPCs) that share many of the same chemical properties of MA and MDMA. Within the last 10 years or so, because of regulatory efforts to curb the use of MA and MDMA, manufacturers and distributors of illicit drugs have turned to the manufacture and distribution of these structurally related SPCs in order to circumvent legal restrictions. SPCs are often described using the general term ?bath salts?, which refers to early marketing strategies used to avoid regulatory oversight prior to the sale of the drugs being made illegal. All of these drugs are now regulated as DEA Schedule 1 drugs, but their use and abuse continues to rise, and the very large number of SPC derivatives with similar subjective effects, but different potentials for adverse effects, present problems for regulators, clinicians, and drug abuse researchers. These newer SPCs have many of the properties desired by users (including the ability to produce psychomotor activation and euphoria), but also have potentially dangerous toxic and lethal effects. We have recently been investigating the lethal effects of these drugs in mouse models, but this work has progressed slowly because of the large number of SPC derivatives, and because drug interactions may be important to their lethal and toxic effects. The development of a higher throughput approach to the evaluation of the relative risks associated with particular SPCs would greatly accelerate this work. This project will (1) develop a high throughput assay for SPC lethality using Zebrafish larvae; (2) use this assay to evaluate the relative risks of a series of related SPC derivatives in order to develop structure activity relationships for lethality; and (3) examine the role of plasma ammonia in the lethal effects of SPCs. This knowledge will provide crucial information about the risks associated with SPC overdose, knowledge about the underlying mechanisms contributing to SPC lethality, and provide an approach that will accelerate investigations of the lethal and toxic effects of this diverse drug class.